IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer
- 1 April 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 18 (4), 549-559
- https://doi.org/10.1158/1541-7786.mcr-19-0956
Abstract
EGFR-mutated lung cancer accounts for a significant proportion of lung cancer cases worldwide. For these cases, osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is extensively used as a 1st or 2nd line treatment. However, lung cancer cells acquire resistance to osimertinib in 1-2 years. Thus, a thorough clarification of resistance mechanisms to osimertinib is highly anticipated. Recent next-generation sequencing (NGS) of lung cancer samples identified several genetically defined resistance mechanisms to osimertinib, such as EGFR C797S or MET amplification. However, non-genetically defined mechanisms are not well evaluated. For thorough clarification of osimertinib resistance, both genetic and non-genetic mechanisms are essential. By using our comprehensive protein phosphorylation array, we detected IGF1R bypass pathway activation after EGFR abolishment. Both of our established lung cancer cells and patient-derived lung cancer cells demonstrated IGF2 autocrine-mediated IGF1R pathway activation as a mechanism of osimertinib resistance. Notably, this resistance mechanism was not detected by a previously performed NGS, highlighting the essential roles of living cancer cells for thorough clarification of resistance mechanisms. Interestingly, the immunohistochemical analysis confirmed the increased IGF2 expression in lung cancer patients who were treated with osimertinib and met the established clinical definition of acquired resistance. The findings highlight the crucial roles of cell-autonomous ligands expression in osimertinib resistance. Here, we report for the first time the IGF2 autocrine-mediated IGF1R activation as a non-genetic mechanism of osimertinib resistance in lung cancer at a clinically relevant level. Implications: Using comprehensive protein phosphorylation array and patient-derived lung cancer cells, we found that IGF2 autocrine-mediated IGF1R pathway activation is a clinically relevant and common mechanism of acquired resistance to osimertinib.Other Versions
Funding Information
- Japan Society for the Promotion of Science (#17K16059, #19J12401)
- Japan Society for the Promotion of Science (#18K08184)
- Japan Society for the Promotion of Science (#18K15251)
- Japan Society for the Promotion of Science (#17K09667)
- Japan Agency for Medical Research andDevelopment (#18ae0101016s0105)
This publication has 44 references indexed in Scilit:
- Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialThe Lancet Oncology, 2012
- Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 studyThe Lancet Oncology, 2011
- Catalytic Control in the EGF Receptor and Its Connection to General Kinase Regulatory MechanismsMolecular Cell, 2011
- A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell SubpopulationsCell, 2010
- Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaThe New England Journal of Medicine, 2009
- Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor SensitivityCancer Cell, 2007
- Epidermal growth factor receptor mutations in lung cancerNature Reviews Cancer, 2007
- An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor ReceptorCell, 2006
- Erlotinib in Previously Treated Non–Small-Cell Lung CancerThe New England Journal of Medicine, 2005
- Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to GefitinibThe New England Journal of Medicine, 2004